Sudden cardiac death is one of the most common cause of mortality worldwide. Despite significant advances in the medical science, there is little improvement in the sudden cardiac death related mortality. Coronary artery disease is the most common etiology behind sudden cardiac death, in the above 40 years population. Even in the apparently healthy population, there is a small percentage of patients dying from sudden cardiac death. Given the large denominator, this small percentage contributes to the largest burden of sudden cardiac death. Identification of this at risk group among the apparently healthy individual is a great challenge for the medical fraternity. This article looks into the causes and methods of preventing SCD and at some of the Indian data. Details of Brugada syndrome, Long QT syndrome, Genetics of SCD are discussed. Recent guidelines on many of these causes are summarised.

Sudden cardiac death [1] (SCD) is natural death from cardiac causes, heralded by abrupt loss of consciousness within 1-h of symptom onset in a person without any prior condition that would appear fatal. Preexisting heart disease may or may not have been known to be present, but time and mode of death are unexpected. In case of unwitnessed arrest time, a frame of 24 h is proposed.

Epidemiology

SCD is responsible for approximately 7 million deaths/year worldwide. This is equivalent to 1–2 deaths/1000 population. SCD have a pattern of the bimodal peak with an initial peak at <1-year of age and second at 45 years to 75 years of age. Thirty percent of all natural deaths are SCDs. Seventy-five percent of SCDs are of cardiac etiology, 18% due to pulmonary embolism, 4% due to aortic rupture, and 3% due to intracranial hemorrhage.[2] SCD is also an important cause of death in patients with preexisting heart disease. Fifty percent of all coronary deaths are SCDs and 30–50% of all heart failure deaths are SCDs.[3] Worldwide no decrease in SCD mortality has been noted over last three decades. Approximately, 50% of all cardiac arrests caused by coronary heart disease occur as the first clinically manifested event, and up to an additional 30% occur in the clinical setting of known disease in the absence of strong risk predictors as depicted in [Table 1]. Less than 25% of victims have high-risk markers based on arrhythmic or hemodynamic parameters. Hence, there is an urgent need for the development of risk stratification models.

Table 1: Distribution of the clinical status of victims at the time of SCD

There is a significant change in epidemiological trends of SCD in the form of progressive decrease in the prevalence of sudden cardiac arrest presenting as ventricular fibrillation (VF) and proportional increase in those presenting with non-VF rhythms (pulseless electrical activity [PEA] and asystole). These changes are seen even with decreases in response time for resuscitation. The possible explanation being as VF most commonly seen in patients with coronary artery disease (CAD), and mortality from CAD had become half over last five decades.

Indian data

The first study evaluating SCD as an endpoint using verbal autopsy showed that SCD contributed to 10.3% of overall mortality. The mean age of SCD cases was significantly lower in this study as compared to studies in the United States and Europe, with 21% of the deaths in people below 50 years of age. One-third of the SCD cases had old myocardial infarction (MI) and 80% of them had risk factors associated with CAD.

At cellular level increased adrenergic drive, hypokalemia, and the abnormal threshold for sodium influx are responsible for increased automaticity in myocytes. Ischemia, myocarditis, and drug toxicities are usual triggering factors for abnormal automaticity.

Triggered activity

Triggered activity due to early after depolarization (EAD) during Phase 2 or 3 of the action potential duration is responsible for TdP and polymorphic VT in long QT syndrome (LQTS). Dyselectrolytemia, hypoxia, acidosis, myocardial injury, cardiac hypertrophy, heart failure, and Class III antiarrhythmic drugs also causes TdP due to EAD. Delayed after depolarizations occurs in Phase 4 of the action potential and are responsible for TdP due to digitalis toxicity, catecholaminergic polymorphic VT (CPVT), left ventricular (LV) hypertrophy (LVH), and heart failure.

Reentry

Reentry typically requires diseased or scarred myocardium as in ischemic heart disease and cardiomyopathies. Brugada syndrome (BrS) and early repolarization (ER) syndrome are also examples of VT/VF due to re-entry.

Whatever the mechanism of initiation of VF, it is coarse at its onset, with tall amplitude and may appear regular at times. These findings may represent an organized ventricular flutter with rates exceeding 260 beats/min. Sometimes early VF may simulate as polymorphic VT. These early findings are referred as Type I VF and may defibrillate spontaneously. With the persistence of VF, there is progressive ischemia and acidosis there is an increase in fibrillation cycle length and prolonged diastole. This is Type II VF where fibrillatory waves become finer and more irregular in amplitude, duration, and cycle length. Sometimes very fine fibrillatory waves may give the appearance of a straight line in ECG without any electrical activity resembling asystole.[8],[9]

Bradyarrhythmia/asystole

This form of SCD is more common in patients with advanced stages of heart disease. Failure of autonomic function to trigger subordinate pacemaking function in the presence of diseased sinoatrial and atrioventricular (AV) node leads to an asystolic arrest. Systemic problems such as hypoxia, acidosis, shock, multi-trauma, and hypothermia may cause loss of automaticity of the conduction system by decreasing the Phase 4 of cardiac action potential mainly by a localized increase in extracellular potassium.[10]

Pulseless electrical activity

PEA or electromechanical dissociation is a term used for the continued rhythmic electrical activity of the heart without any effective cardiac mechanical contraction. Mechanical problems such as massive pulmonary embolism, prosthetic valve dysfunction, obstructing ball valve thrombus, or tumor, cardiac tamponade are reasons for abrupt cessation of cardiac venous return and results in secondary PEA. In primary PEA, there are no mechanical issues, but electrical activity fails to produce an effective myocardial contraction. Advanced and diffuse heart disease, metabolic abnormalities, global ischemia are common causes for PEA. Abnormal cellular calcium, acidosis, or adenosine triphosphate depletion are possible mechanisms at the cellular level for PEA [Table 2].[11]

Prodromal symptoms in the form of chest pain, dyspnea, fatigue, palpitations, or syncope may be present is a significant population of patients experiencing SCD. Most of these symptoms are nonspecific and may be present from days to months before the SCD. Symptoms that immediately precede SCD are more specific and are usually observed minute to hours before the event. Increased heart rate, increased ventricular ectopy along with changes in the autonomic tone are frequent. Actual terminal event or cardiac arrest is a loss of consciousness secondary to cerebral ischemia due to inadequate pumping of blood by the heart. Most of these patients will witness one of the above-mentioned reasons as the cause for pump failure. A minority of patients may survive this event. Data from a large registry data suggests that 14% patients survived an in-hospital cardiac arrest.[12]

Specific Conditions

Coronary artery disease

Approximately, 65–70% of all SCDs belong to this group. In younger age group (<40 years) this is the less common cause of death 30–50% of all MI deaths are SCDs and usually occur within a 1st hour of MI onset. Occlusion of left anterior descending or circumflex artery is more likely to cause SCD than that of right coronary artery. Among all SCDs occurring without any warning signs, 50% have occluded artery on angiography.[13] Among patients with ST-segment elevation MI (STEMI), the incidence of VT/VF is 10% with 80–85% occurring in the first 48 h. The overall incidence of VT/VF in non-STEMI patients is 2% with a peak at 78 h.[14],[15],[16] Late SCD after MI is usually related to scar-related VT/VF and usually occurs within the 1st year of MI. VT/VF during the acute phase of MI (<48 h) are not predictive of late events in the absence of recurrent ischemia. High-risk features include previous cardiac arrest, syncope, MI within 6 months, ejection fraction of <30–35%, and frequent ventricular ectopy (>10 premature ventricular contractions per hour or nonsustained VT (NSVT)). Clustering of specific risk factors such as age, diabetes mellitus, smoking, heart rate, systolic blood pressure (BP), relative weight, vital capacity, and serum cholesterol are also a risk for SCD. Fifty percent of all SCDs occur in the 10% of the population in highest risk decile.[17] Coronary artery anomalies, coronary embolism, arteritis, external compression of coronaries, and coronary vasospasm are other coronary related causes of SCD.

Nonischemic cardiomyopathy

Heart failure/left ventricular dysfunction

Heart failure irrespective of its etiology is a risk factor for SCD. Progressive pump failure, sudden arrhythmic death, and arrhythmic death during the period of clinical worsening each are responsible for one-third of deaths. In some patients, acute coronary event may be preceding cause for SCD. High-risk factors include previous cardiac arrest, syncope, and an ejection fraction of < 30–35%, VT on holter, poor functional grade, and use of inotropic medications. Autonomic dysfunction, repolarization abnormalities of ECG and inducible VT on electrophysiological (EP) study are potential risk factors for SCD.

Hypertrophic cardiomyopathy

High-risk factors for SCD includes the young age of onset, LV mass, family history of SCD, ventricular arrhythmias, abnormal BP response during exercise, and history of syncope. High resting gradients, provocable arrhythmias on EP study, late gadolinium enhancement on cardiac magnetic resonance imaging and certain genetic mutations are also important risk factors. Electrical instability secondary to hypertrophied muscle mass is a much more common mechanism of SCD than hemodynamic instability secondary of dynamic obstruction. In athletes younger than 35 years of age hypertrophic cardiomyopathy (HCM) is the most common cause of SCD. Half of SCDs in HCM are during exercise.[18]

Left ventricular hypertrophy

LVH irrespective of its cause is an independent risk factor of SCD.

Arrhythmogenic right ventricular dysplasia

In ARVC, there is progressive replacement of right ventricle with fatty and fibrous tissue. Its prevalence is 1 in 5000 with autosomal dominant inheritance except in a specific population where inheritance is autosomal recessive (Naxos disease). Ten percent of SCD in individuals younger than 35 years age are due to ARVC. The median age of presentation is 26 years and presenting symptoms are palpitations, syncope, and SCD. Abnormal ECG is present in > 90% of patients with ARVC. Exercise can precipitate VT in ARVC. The annual incidence of SCD is estimated to be 1%. The highest risk for arrhythmic death include survival from SCD, syncope, family history of SCD, spontaneous VT/NSVT, marked right ventricular (RV) involvement, and LV involvement.[19],[20]

Miscellaneous

Myocarditis, infiltrative cardiomyopathies (amyloidosis, sarcoidosis) are also important causes of SCD independent of the degree of ventricular dysfunction.

Valvular heart disease

Among the valvular lesions, aortic stenosis has the highest risk of SCD. Other stenotic lesions such as pulmonary stenosis and mitral stenosis have a lesser risk for SCD.[21] Chronic regurgitant lesions have lesser SCD risk than stenotic lesions. After valve replacement surgery, the risk of SCD is high for first few months. The incidence of SCD with mitral valve prolapse (MVP) is also low. High-risk features with MVP are a marked redundancy of mitral leaflet, the presence of mitral regurgitation, complex ventricular ectopy, history of embolism and ST-T changes in the inferior leads.[22] Infective endocarditis of left-sided valves may cause SCD due to acute mechanical complications such as valve perforation, coronary embolism etc.

Congenital heart disease

Congenital valvular stenosis is associated with high-risk of SCD. Lesions with severe pulmonary arterial hypertension and eisenmenger complex are also at high-risk of SCD. Oxygen saturation of < 80% is a risk factor for SCD. Certain CHDs are at high-risk of SCD late after their repairs such as tetralogy of Fallot (TOF), Transpostion of Great Arteries (TGA), and AV canal defect. High-risk marker in repaired TOF are syncope, VT, RV function, QRS duration and rate of progression of QRS duration widening.[23]

Commotio cordis

Blunt nonpenetrating chest blows during athletic or recreational activities that cause SCD is termed as commotio cordis. It is the second leading cause of SCD in youth sports. Sports in which projectiles are integral to the game (youth baseball, softball, ice hockey, and football) are the more likely culprit. Collapse is instantaneous in one-half of the sufferers and within 5 to 20 s in the others. Cardiac arrhythmias documented soon after collapse are generally VF and resuscitation is more difficult despite a structurally normal heart. Important determinants of VF after a chest blow are timing of impact relative to the cardiac cycle and peak LV pressures caused by the blow. KATP ion channel mediates the initiation of VF and chest protectors did not appear to reduce the risk of VF.[24]

Conduction system abnormalities

Complete heart block either due to acquired (Lev's and Lenegre's disease) or congenital causes are also important treatable causes of SCD. The presence of symptoms and lower escape rates are important predictors for SCD. The presence of accessory pathway with shorter refractory period allows very fast ventricular rate in the presence of atrial fibrillation. Such fast rates may readily degenerate into VF and SCD. A refractory period of <250 ms, the presence of multiple pathways and family history of SCD are considered as high-risk for SCD.[25] SVTs such as AV reentry tachycardia and AV nodal reentrant tachycardia have overall very low risk of SCD.

Primary arrhythmia syndrome

Brugada syndrome (BrS)

BrS is an autosomal dominant disorder with highly variable penetrance and expression. It generally involves young men with arrhythmia first occurring at an average age of 40 years. Sudden death typically occurs during sleep/rest. Typical ECG pattern in a symptomatic patient with structurally normal heart is diagnostic of BrS [Figure 1]. The prevalence of the Brugada-type ECG was found in 98 of 13,929 study subjects (0.70%) in a Japanese study.[26] Brugada ECG pattern is highly variable over time. In patients with spontaneous coved-type ECG, only every third ECG is diagnostic, and every third ECG is normal. Placing the V1–V2 recording electrodes at the second or third intercostal space increases the odds for recording a Type I pattern. With 24-h Holter recordings, one may detect transient Type I ST-segment elevation. When undertaking provocative testing with a sodium channel blocker, the drug should be stopped when a Type I ECG develops, ventricular premature beats (VPBs), other arrhythmias, or the QRS widens to 130% of baseline. Provocative testing is more useful for diagnosis and do not carry much significance with regards to risk stratification. About 2% patient may develop sustained ventricular arrhythmias requiring defibrillation during testing.[27]

Figure 1: Three types of Brugada electrocardiogram pattern in lead V2.

The incidence of LQTS is 1/2500 persons. Patients usually present with TdP/VT, which if prolonged may [28],[29] cause syncope, cardiac arrest or SCD. Resting ECG may/may not show prolonged QT and 50% of individuals experiencing SCD from this disorder may have exhibited prior warning signs. Twenty percent of autopsy-negative sudden unexplained deaths in the young and 10% of sudden infant death syndrome (SIDS) cases are due to LQTS. Intravenous epinephrine challenge is useful in bringing out LQTS if resting ECG is showing normal QTc. Other causes of abnormal prolongation of the QT such as myocardial ischemia, cardiomyopathies, hypokalemia, hypocalcemia, hypomagnesemia, autonomic influences, drug effects, and hypothermia should also be kept in mind. Sixteen genes have so far been identified as responsible for LQTS. LQTS 1, 2, and 3 are caused by mutation of KCNQ1, KVNH2, and SCNA5, respectively, and account for 75% of all LQTS. High-risk factors include female gender, a greater degree of QT prolongation (>500 ms), QT alternans, unexplained syncope, documented TdP/VF and family history of premature SCD. High dose beta-blockers, left cervical sympathetic denervation, and intracardiac defibrillator (ICD) are the cornerstone of the treatment for congenital LQTS [Table 3] and [Table 4].[28]

Short QT syndrome (SQTS) is diagnosed in the presence of a QTc ≤ 330 ms. SQTS can be diagnosed with QTc ≤ 360 in the presence of a pathogenic mutation, family history of SQTS, family history of sudden death at age ≤40 years or survival of a VT/VF episode in the absence of heart disease. In 53 patients from the European short QT registry average, QTc was 314 ms and sudden death was the clinical presentation in 32%. The event rate was 4.9%/year in the patients without antiarrhythmic therapy, and no arrhythmic events occurred in patients receiving hydroquinidine.[30] ICD implantation is recommended in symptomatic SQTS who are survivors of a cardiac arrest and/or have documented spontaneous sustained VT. Quinidine/sotalol is recommended in asymptomatic patients and a family history of SCD.

Catecholaminergic polymorphic ventricular tachycardia (CPVT)

CPVT classically manifests with exercise-induced syncope or sudden death in young and prevalence of the disease could be as high as 0.1:1000. It closely mimics the phenotypic of LQT1. Fifteen percent of autopsy-negative sudden unexplained death in the young is due to CPVT. It is diagnosed in the presence of a structurally normal heart, normal ECG, and unexplained, exercise or catecholamine-induced bidirectional VT or polymorphic VPBs or VT in an individual younger than 40 years. In an individual older than 40 years, CPVT can be diagnosed in the presence of a structurally normal heart and coronary arteries, normal ECG, an unexplained exercise or catecholamine-induced bidirectional VT or polymorphic VPBs or VT. Swimming is potentially lethal in these patients. Treatment includes lifestyle changes such as avoiding competitive sports and strenuous exercise, beta-blockers, and ICD implantation. Flecainide and left cervical sympathetic denervation are additional treatment modalities.[31]

Idiopathic ventricular fibrillation

Idiopathic VF (IVF) is diagnosed in a resuscitated cardiac arrest victim, particularly if there is documentation of VF, in whom known cardiac, respiratory, family history of conduction abnormalities, pacemaker implants, or metabolic, and toxicological etiologies have been excluded. Most of the unexplained cardiac arrests will fall in this category. Inferolateral ER pattern has been associated with risk of IVF. J point elevation of more than 1 mm in two contiguous inferolateral leads is diagnostic of ER. It is present in 1–13% of general population and 15–70% of IVF cases. High-risk features include a family history of SCD, arrhythmic syncope, and magnitude (>0.2 mV) and morphology (slurred or notched J point with horizontal or descending ST-segment) of the ER pattern. ICD is recommended for SCD survivors.[32] Isoprenaline infusion is helpful in taming the VT storms.

Sudden infant death syndrome

Sudden unexplained deaths among kids of < 1-year age are termed as SIDS. The incidence of SIDS is 59/100,000 among children younger than 1-year. Obstructive sleep apnea is predominant reason for SIDS and teaching appropriate sleep position is to mother is helpful in preventing many potential SIDS.[33] Ten percent of all SIDS are due to LQTS. BrS, accessory pathways, premature AV nodal or bundle branch cells, congenital heart disease, and myocarditis are other causes of SIDS.

Athletes

SCD may rarely be associated with competitive athletic activity in young and apparently healthy individuals. Malignant cardiac arrhythmias are the underlying mechanism in majority. Strenuous physical activity induces cardiac interstitial fibrosis that may create arrhythmic substrate, and the immediate physiologic demands of competitive athletics may trigger malignant arrhythmias and SCD in susceptible individuals with underlying cardiac abnormalities.[34] There is some observational data to suggest a benefit of screening before starting competitive athletic activity, and both American College of Cardiology and European Society of Cardiology recommend screening for athletes.

Genetics of sudden cardiac death

In addition to mutations in known SCD genes, several genes not previously implicated in SCD causation have been found, particularly in LQTS (KCNJ5, AKAP9, and SNTA1), IVF (DPP6, KCNJ8), dilated cardiomyopathy (NEBL) and HCM (NEXN). Genetic SCD animal models have provided insights into the cellular mechanism of these syndromes. Genetic contributions to acquired heart diseases are also being recognized. For instance, a 21q21 locus is linked to VF after MI. Near this locus is CXADR, a gene encoding a viral receptor implicated in myocarditis and dilated cardiomyopathy. Genetic testing effects care of inherited SCD syndrome patients and also their asymptomatic and disease-carrying relatives by the institution of prophylactic treatment.

Prevention and Treatment

Primary prevention

Primary prevention for the general population without known cardiac disease includes screening and management of risk factors for CHD (e.g. measurement of lipids, BP, and glucose). By far, this remains the most cost-effective strategy to prevent SCD in the general population. A heart-friendly lifestyle includes regular physical activity, a heart-healthy diet, and cessation of tobacco consumption and is recommended for the primary prevention of SCD. Patients with the known cardiac disease (MI, LV dysfunction, or heart failure) are at an increased risk of SCD. Apart from standard medical therapy some of these patients need further evaluation for ICD implantation. Patients in post-MI phase are implanted ICD only after 40 days as two major randomized control trial IRIS [35] and DINAMIT [36] failed to show benefit of ICD in first 6–40 days after MI due to increase in nonarrhythmic death in intervention arm in these trials. [Table 5] highlights the common indication of ICD in primary prevention.[37]

The management of SCD includes acute treatment and for the survivors of SCD a comprehensive evaluation and secondary prevention is required. The acute management of SCD is basically standard cardiopulmonary resuscitation protocols. Management of survivors of SCD includes the identification and treatment of reversible causes, evaluation for structural heart disease and/or primary electrical diseases, neurologic and psychologic assessment, and evaluation of family members in selected cases. Routine angiography and revascularization have been suggested in all patients surviving from out of hospital cardiac arrest.[38],[39] ICD is indicated in almost all cases for secondary prevention of SCD.

Conclusion

SCD remains an important public health problem [40] and an enigma for cardiologists. It is also one of the most devastating complications with many apparently young and healthy people falling as its prey. Despite deciphering many secrets of SCD in recent years, many of its aspects are veiled, and the need continues efforts from various fraternities in the medical field for complete understanding.

Zipes DP, Camm AJ, Borggrefe M, Buxton AE, Chaitman B, Fromer M, et al. ACC/AHA/ESC 2006 guidelines for management of patients with ventricular arrhythmias and the prevention of sudden cardiac death: A report of the American College of Cardiology/American Heart Association Task Force and the European Society of Cardiology Committee for Practice Guidelines (Writing Committee to develop Guidelines for management of patients with ventricular arrhythmias and the prevention of sudden cardiac death): Developed in collaboration with the European Heart Rhythm Association and the Heart Rhythm Society. Circulation 2006;114:e385-484.